EYA2 (EYA transcriptional coactivator and phosphatase 2)

Department of Biochemistry, Molecular Genetics, Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA

Abstract

EYA2 encodes a co-activator for the SIX family of homeobox transcription factors. The SIX/EYA transcriptional complex plays important roles in organogenesis, promoting the proliferation and survival of progenitor cells. Abnormal re-expression of EYA2 in adult tissue promotes tumorigenesis and metastasis in multiple tumor types. In addition to its role as a co-activator, the EYA Domain (ED) of EYA2 contains a unique HAD family Tyr phosphatase activity, which plays a role in ERβ specific anti-tumor activity in breast cancer. The EYA2 Tyr phosphatase can also dephosphorylate H2AX, potentially playing a role in DNA damage repair. The N-terminal region of EYA2 also contains a Ser/Thr phosphatase activity, which may regulate the innate immune response.

The transcript of EYA2 gene is 2702 bp long. Coding sequence of EYA2 starts at the 375th bp and ends at the 1991st bp of the mRNA.

Pseudogene

No pseudogene has been reported for EYA2.

Protein

A schematic representation of the EYA2 protein that contains a flexible N-terminal region and a highly conserved C-terminal EYA domain (ED).

Description

The EYA2 gene encodes a 538 amino acid protein with a predicted molecular weight of 59 kDa. It is composed of a flexible N-terminal region and a highly conserved C-terminal EYA domain (ED). The N-terminal region is poorly conserved among EYA family members (EYA1, EYA2, EYA3 and EYA4) and the lengths of the N-terminal region in EYA2 vary amongst species. The N-terminal region contains a Pro/Ser/Thr rich transactivation domain that is responsible for activating SIX-mediated transcription (Xu et al., 1997a; Ohto et al., 1999). The N-terminal region of all mouse EYA family members have been shown to possess Ser/Thr phosphatase activity, and this activity of EYA4 was shown to play a role in regulating the innate immune response (Okabe et al., 2009; Sano and Nagata, 2011). The highly conserved C-terminal ED mediates the interaction between EYA2 and its protein partners, including SIX1 (Patrick et al., 2013). The ED of EYA2 also contains Mg2+-dependent Tyr phosphatase activity (Krishnan et al., 2009; Yuan et al., 2014). Crystal structures of both the ED of human EYA2 and the SIX1/EYA2 ED complex have been determined, providing detailed structural information for the C-terminal half of EYA2 (Jung et al., 2010; Patrick et al., 2013).

Expression

To date, there has been no investigation of EYA2 protein levels in different developmental stages or tissues, but the mRNA transcripts of EYA2 have been examined by Northern blot, real time RT-PCR or in situ hybridization. In general, EYA2 expression is high and widespread in embryo and is low and limited in adult tissues. In situ hybridization in mouse embryo detected Eya2 in facioacoustic ganglionic complex, epibranchial placodes, nasal placodes, somites, branchial arch ectoderm, the trigeminal, dorsal root ganglia, cranial placodes, central nervous system, neural retina, sclera, optic nerve sheath (Xu et al., 1997b), and the tendons and ligaments of the limb (Xu et al., 1997a). EYA2 expression in limb displayed a pattern similar to that of SIX1. In newborn mice, EYA2 was detected using Northern blot in the eye, brain, and lung at high levels, but was not detected in the skin, liver, intestine, and kidney (Duncan et al., 1997). In adult mice, EYA2 mRNA remains at high levels in the eye lens, and is decreased in the lung and brain based on Northern blot analyses (Duncan et al., 1997). EYA2 mRNA can also be detected in thymus and uterus (Zimmerman et al., 1997). In adult humans, EYA2 was predominantly observed in muscle, and at lower levels in kidney, placenta, brain, and pancreas based on Northern blot analyses (Duncan et al., 1997). RT-PCR revealed EYA2 mRNAs in human testis, colon, thymus, thyroid and prostate (Zhang et al., 2005).